Harnessing FBXO31 with terminal amide-functionalized molecules for targeted protein degradation
Zhang, C.; Jin, X.; Zhou, C.; Martin, J. M.; Riha, I. A.; Zhang, X.
Show abstract
Targeted protein degradation (TPD) is a powerful strategy for controlling protein abundance. Here, we establish FBXO31 as a TPD-competent E3 ligase by exploiting its recognition of C-terminal amide-bearing degrons. Using an amidated Ala-Phe motif as a chemical recruiter, multiple small-molecule binders can be transformed into FBXO31-dependent degraders that induce rapid and potent target degradation. Mechanistic studies confirm FBXO31-mediated ternary complex formation and identify key residues in FBXO31 required for recruiter engagement and target degradation. We further show that an FBXO31-based multi-kinase degrader exhibits a distinct and broader degradation profile than a CRBN-based degrader, highlighting a potentially expanded degradable target space beyond CRBN.
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